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Science 15 October 1993:
Vol. 262. no. 5132, pp. 419 - 421
DOI: 10.1126/science.8211162
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Articles

Science, Vol 262, Issue 5132, 419-421
Copyright © 1993 by American Association for the Advancement of Science

articles

Converting tissue plasminogen activator to a zymogen: a regulatory triad of Asp-His-Ser

EL Madison, A Kobe, MJ Gething, JF Sambrook, and EJ Goldsmith

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235.

Unlike most serine proteases of the chymotrypsin family, tissue-type plasminogen activator (tPA) is secreted from cells as an active, single-chain enzyme with a catalytic efficiency only slightly lower than that of the proteolytically cleaved form. A zymogenic mutant of tPA has been engineered that displays a reduction in catalytic efficiency by a factor of 141 in the single-chain form while retaining full activity in the cleaved form. The residues introduced in the mutant, serine 292 and histidine 305, are proposed to form a hydrogen-bonded network with aspartate 477, similar to the aspartate 194-histidine 40-serine 32 network found to stabilize the zymogen chymotrypsinogen.


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